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nf κb signaling is required for xbp1 unspliced and spliced mediated effects on Antiestrogen responsiveness and cell fate decisions in breast cancer

Antiestrogen therapy induces the unfolded protein response (UPR) in estrogen receptor-positive (ER(+)) breast cancer. X-box binding protein 1 (XBP1), which exists in the transcriptionally inactive unspliced form [XBP1(U)] and the spliced active form [XBP1(S)], is a key UPR component mediating Antiestrogen resistance. We now show a direct link between the XBP1 and NF-κB survival pathways in driving the cell fate decisions in response to Antiestrogens in ER(+) breast cancer cells, both in vitro and in a xenograft mouse model. Using novel spliced and nonspliceable forms of XBP1, we show that XBP1(U) functions beyond being a dominant negative of XBP1(S). Both isoforms regulate NF-κB activity via ERα; XBP1(S) is more potent because it also directly regulates p65/RelA expression. These findings provide new insights into the fundamental signaling activities of spliced and unspliced XBP1 in breast cancer, establish NF-κB to be a mediator of these activities, and identify XBP1 and its splicing to be novel therapeutic targets.

abstract 679 glutamine metabolism in myc driven Antiestrogen resistant breast cancer cells confers metabolic flexibility through the unfolded protein response

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA

Antiestrogens are used to treat estrogen receptor positive (ER+) breast tumors that constitute 70% of all breast cancer cases. Unfortunately, acquired resistance to Antiestrogen therapy remains a critical clinical obstacle. Here we show that human breast cancer cells and rat mammary tumors that have acquired resistance to Antiestrogens express increased levels of MYC, a major regulator of both glutamine and glucose. Glutamine metabolism and glucose uptake were elevated in ER+ Antiestrogen resistant cells (LCC9) compared with sensitive cells (LCC1). Inhibition of MYC, with siRNA or small molecule inhibitor, reduced cell viability and uptake of both glutamine and glucose in resistant cells. In resistant cells, MYC expression controlled protein levels of glutamine, glutamate and glucose transporters as well as GLUL and GLS, two enzymes that promote glutamate-glutamine inter-conversion. Increased MYC function in resistant cells correlated with increased cellular sensitivity to deprivation of, and also inhibitors of, both glutamine and glucose. While apoptosis eliminated all resistant cells in glucose-only conditions beyond 72 h, in glutamine-only conditions, the unfolded protein response (UPR) via GRP78-IRE1α and activating JNK and increased CHOP, induced apoptosis in majority of the cells but promoted survival in some. The Antiestrogen faslodex (FAS; ICI 182,780) significantly reduced glucose uptake in Antiestrogen resistant cells compared with sensitive cells. Thus, our findings reveal unique roles for MYC in promoting metabolic flexibility in and promoting survival in Antiestrogen resistant breast cancer cells via the UPR. Targeting glutamine and glucose metabolism pathways, therefore, may provide novel strategies in treating endocrine resistant breast cancers.

Citation Format: Ayesha N. Shajahan-Haq, Katherine L. Cook, Jessica L. Schwartz-Roberts, Ahreej E. Eltayeb, Diane M. Demas, Anni M. Warri, Leena A. Hilakivi-Clarke, Robert Clarke. Glutamine metabolism in MYC-driven Antiestrogen resistant breast cancer cells confers metabolic flexibility through the unfolded protein response. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 679. doi:10.1158/1538-7445.AM2014-679

knockdown of estrogen receptor α induces autophagy and inhibits Antiestrogen mediated unfolded protein response activation promoting ros induced breast cancer cell death

Approximately 70% of all newly diagnosed breast cancers express estrogen receptor (ER)-α. Although inhibiting ER action using targeted therapies such as fulvestrant (ICI) is often effective, later emergence of Antiestrogen resistance limits clinical use. We used Antiestrogen-sensitive and -resistant cells to determine the effect of Antiestrogens/ERα on regulating autophagy and unfolded protein response (UPR) signaling. Knockdown of ERα significantly increased the sensitivity of LCC1 cells (sensitive) and also resensitized LCC9 cells (resistant) to Antiestrogen drugs. Interestingly, ERα knockdown, but not ICI, reduced nuclear factor (erythroid-derived 2)-like (NRF)-2 (UPR-induced antioxidant protein) and increased cytosolic kelch-like ECH-associated protein (KEAP)-1 (NRF2 inhibitor), consistent with the observed increase in ROS production. Furthermore, autophagy induction by Antiestrogens was prosurvival but did not prevent ERα knockdown–mediated death. We built a novel mathematical model to elucidate the …

comparison of the effects of em 652 sch57068 tamoxifen toremifene droloxifene idoxifene gw 5638 and raloxifene on the growth of human zr 75 1 breast tumors in nude mice

EM-652 exerts pure Antiestrogenic activity in the mammary gland and endometrium, while tamoxifen, the Antiestrogen most widely used for the treatment of breast cancer, exerts mixed Antiestrogenic-estrogenic activity in these tissues. Our objective was to compare the agonistic and antagonistic effects of EM-652 with tamoxifen and 5 other Antiestrogens on the growth of ZR-75-1 human breast xenografts in ovariectomized nude mice. During the 23 weeks of treatment at a daily oral dose of 50 microg, EM-652 was the only compound that decreased tumor size relative to pretreatment values, whereas the 6 other Antiestrogens only decreased to various extents the progression rate stimulated by estrone. Under estrone stimulation, all groups of animals had more than 60% of their tumors in the progression category except for the EM-652-treated group, where only 7% of the tumors progressed. In the absence of estrone stimulation, progression was seen in 60%, 33%, 21% and 12% of tumors in the tamoxifen-, idoxifene-, toremifene- and raloxifene-treated groups, respectively, while only 4% of tumors progressed in the EM-652-treated group. The agonistic and antagonistic actions of each Antiestrogen were also measured on endometrial epithelial cell thickness. Our present findings indicate that EM-652, in addition to being the most potent Antiestrogen on human breast tumor growth, has no agonistic effect in breast and endometrial tissues. Since previous data have shown benefits of EM-652 on bone density and lipid profile, this compound could be an ideal candidate for chemoprevention of breast and uterine cancers, while protecting against osteoporosis and cardiovascular disease.

comparison of the effects of em 652 sch57068 tamoxifen toremifene droloxifene idoxifene gw 5638 and raloxifene on the growth of human zr 75 1 breast tumors in nude mice

EM-652 exerts pure Antiestrogenic activity in the mammary gland and endometrium, while tamoxifen, the Antiestrogen most widely used for the treatment of breast cancer, exerts mixed Antiestrogenic–estrogenic activity in these tissues. Our objective was to compare the agonistic and antagonistic effects of EM-652 with tamoxifen and 5 other Antiestrogens on the growth of ZR-75-1 human breast xenografts in ovariectomized nude mice. During the 23 weeks of treatment at a daily oral dose of 50 μg, EM-652 was the only compound that decreased tumor size relative to pretreatment values, whereas the 6 other Antiestrogens only decreased to various extents the progression rate stimulated by estrone. Under estrone stimulation, all groups of animals had more than 60% of their tumors in the progression category except for the EM-652–treated group, where only 7% of the tumors progressed. In the absence of estrone stimulation, progression was seen in 60%, 33%, 21% and 12% of tumors in the tamoxifen-, idoxifene-, toremifene- and raloxifene-treated groups, respectively, while only 4% of tumors progressed in the EM-652–treated group. The agonistic and antagonistic actions of each Antiestrogen were also measured on endometrial epithelial cell thickness. Our present findings indicate that EM-652, in addition to being the most potent Antiestrogen on human breast tumor growth, has no agonistic effect in breast and endometrial tissues. Since previous data have shown benefits of EM-652 on bone density and lipid profile, this compound could be an ideal candidate for chemoprevention of breast and uterine cancers, while protecting against osteoporosis and cardiovascular disease. © 2002 Wiley-Liss, Inc.

estrogen receptor alpha somatic mutations y537s and d538g confer breast cancer endocrine resistance by stabilizing the activating function 2 binding conformation

Around one in every eight women will be diagnosed with breast cancer in their lifetime. Hormone-based therapies – also referred to Antiestrogen drugs – target a protein called estrogen receptor alpha and are effective treatments for the majority of these cancers. Unfortunately, about half of patients will develop recurrent breast cancers even though the cancer continues to produce the target of the drugs. The estrogen receptor alpha drives breast cancer in a number of ways, many of which require the receptor to be activated by binding to the hormone estrogen. When estrogen binds it causes the receptor to change shape to expose a surface where other proteins called coactivators can bind. Once a coactivator is bound, the estrogen receptor is active and signals the cancer cell to grow, divide, invade local tissues, and spread to new sites in the body. Antiestrogen drugs competitively block the binding of estrogen to the receptor and cause the receptor to take on a different shape that inhibits the binding of the coactivator. However, recent studies identified mutations at specific sites in the gene that encodes estrogen receptor alpha in a large subset of patients with breast cancers that have spread. These mutations make the receptor resistant to Antiestrogen drugs, and two mutations (called Y537S and D538G) account for approximately 70% of cases. However, it was not clear how these mutations altered the activity of estrogen receptor alpha at the molecular level. Fanning, Mayne, Dharmarajan et al. now show these two most common mutations allow estrogen receptor alpha to bind to the coactivator in the absence of hormone. This unfortunately also reduces the effectiveness of one of the mostly widely administered Antiestrogen therapies – a drug called tamoxifen. However, Fanning, Mayne, Dharmarajan et al. also show that the newer and more potent Antiestrogens that are currently under examination in clinical trials should be highly effective at treating the cancers with the mutated versions of estrogen receptor alpha. Applying the knowledge gained from these new findings toward the development of new Antiestrogens could help reverse the impact of these common mutations. If successful, these new drugs will provide life-saving treatments for many breast cancer patients.

Antiestrogens: Mechanisms of action and resistance in breast cancer

Antiestrogens have proven to be highly effective in the treatment of hormone-responsive breast cancer. However, resistance to Antiestrogen therapy often develops. In addition, although tamoxifen-like Antiestrogens are largely inhibitory and function as estrogen antagonists in breast cancer cells, they also have some estrogen-like activity in other cells of the body. Thus, recent efforts are being directed toward the development of even more tissue-selective Antiestrogens, i.e. compounds that are Antiestrogenic on breast and uterus while maintaining the beneficial estrogen-like actions on bone and the cardiovascular system. Efforts are also being directed toward understanding ligand structure-estrogen receptor (ER) activity relationships and characterizing the molecular changes that underlie alterations in parallel signal transduction pathways that impact on the ER. Recent findings show that Antiestrogens, which are known to exert most of their effects through the ER of breast cancer cells, contact a different set of amino acids in the hormone binding domain of the ER than those contacted by estrogen, and evoke a different receptor conformation that results in reduced or no transcriptional activity on most genes. Resistance to Antiestrogen therapy may develop due to changes at the level of the ER itself, and at pre- and post-receptor points in the estrogen receptor-response pathway. Resistance could arise in at least four ways: (1) ER loss or mutation; (2) Post-receptor alterations including changes in cAMP and phosphorylation pathways, or changes in coregulator and transcription factor interactions that affect the transcriptional activity of the ER; (3) Changes in growth factor production/sensitivity or paracrine cell-cell interactions; or (4) Pharmacological changes in the Antiestrogen itself, including altered uptake and retention or metabolism of the Antiestrogen. Model cell systems have been developed to study changes that accompany and define the Antiestrogen resistant versus sensitive breast cancer phenotype. This information should lead to the development of Antiestrogens with optimized tissue selectivity and agents to which resistance may develop more slowly. In addition, Antiestrogens which work through somewhat different mechanisms of interaction with the ER should prove useful in treatment of some breast cancers that become resistant to a different category of Antiestrogens.

Antiestrogens: Mechanisms of action and resistance in breast cancer

Antiestrogens have proven to be highly effective in the treatment of hormone-responsive breast cancer. However, resistance to Antiestrogen therapy often develops. In addition, although tamoxifen-like Antiestrogens are largely inhibitory and function as estrogen antagonists in breast cancer cells, they also have some estrogen-like activity in other cells of the body. Thus, recent efforts are being directed toward the development of even more tissue-selective Antiestrogens, i.e. compounds that are Antiestrogenic on breast and uterus while maintaining the beneficial estrogen-like actions on bone and the cardiovascular system. Efforts are also being directed toward understanding ligand structure-estrogen receptor (ER) activity relationships and characterizing the molecular changes that underlie alterations in parallel signal transduction pathways that impact on the ER. Recent findings show that Antiestrogens, which are known to exert most of their effects through the ER of breast cancer cells, contact a different set of amino acids in the hormone binding domain of the ER than those contacted by estrogen, and evoke a different receptor conformation that results in reduced or no transcriptional activity on most genes.